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WO2020210428A1 - Nouveaux inhibiteurs de protéase de flavivirus pour la prévention et le traitement du zika, de la dengue et d'autres infections à flavivirus - Google Patents

Nouveaux inhibiteurs de protéase de flavivirus pour la prévention et le traitement du zika, de la dengue et d'autres infections à flavivirus Download PDF

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Publication number
WO2020210428A1
WO2020210428A1 PCT/US2020/027374 US2020027374W WO2020210428A1 WO 2020210428 A1 WO2020210428 A1 WO 2020210428A1 US 2020027374 W US2020027374 W US 2020027374W WO 2020210428 A1 WO2020210428 A1 WO 2020210428A1
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groups
phenyl
combinations
administration
composition
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Inventor
Yongcheng Song
Rebecca Rodea RICO-HESSE
Yuan Yao
Tong HUO
Yi-lun LIN
Fangrui WU
Shenyou NIE
Jing-Yu Wu
Yuanda HUA
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Baylor College of Medicine
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Baylor College of Medicine
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/007—Pulmonary tract; Aromatherapy
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure pertains to a composition.
  • the composition has one or more compounds defined generally as:
  • R 1 , R 2 , and R 3 can each independently include, without limitation, hydrogen, aromatic groups, phenyl groups, benzyl, furan groups, phenyl furan groups, pyridine groups, phenyl pyridine groups, biphenyl groups, phenyl piperidine groups, pyrazole groups, amine groups, piperidine groups, amine groups, alkyl amine groups, aniline groups, methyl piperidine groups, benzene groups, cyclohexane groups, methyl benzoate groups, benzyl piperidine groups, imidazole groups, piperidine amine groups, -NHCH 3 groups, - CH(CH 3 )CH 2 CH 2 NH 2 groups, -NH 2 groups, furan, 3-phenylfuran, 2-phenylfuran, 3- phenyloxolane, phenylmethanamine, propan-2-ylbenzene, tert-butylbenzene, pheny
  • Y includes, without limitation, N, CH, or combinations thereof.
  • Z includes, without limitation, N, CH, or combinations thereof.
  • m is an integer greater than or equal to 0.
  • the viral infection is caused by a flavivirus that includes, without limitation, dengue virus, West Nile virus, Zika virus, tick-borne encephalitis virus, yellow fever virus, viruses causing encephalitis, insect-specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof DESCRIPTION OF THE DRAWINGS
  • a flavivirus that includes, without limitation, dengue virus, West Nile virus, Zika virus, tick-borne encephalitis virus, yellow fever virus, viruses causing encephalitis, insect-specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof
  • FIGURE 1A illustrates a general composition structure according to embodiments of the present disclosure.
  • FIGURE 1B depicts a method of treating a viral infection in a subject.
  • FIGURES 2A-F illustrate X-ray structures of the DV2pro-9 complex.
  • FIG. 2A illustrates the overall structure of the DV2pro in complex with compound 9 (ball and stick model with C atoms in brown).
  • NS3 is shown in green and NS2B in purple.
  • FIG.2B illustrates the 2Fo- F c electron density map of DV2pro-9 at the inhibitor binding site (contoured at 1s) and
  • FIG.2C illustrates the Fo-Fc omit map (at 3s).
  • FIG. 2D shows compound 9 is located in an L-shaped, deep pocket of NS3 (shown as an electrostatic surface) that is mostly hydrophobic.
  • FIG. 2E shows aligned structures of DV2pro-9 with the substrate-bound DV3pro (PDB: 3U1I, NS3 in cyan and NS2B in yellow), showing 9 occupies a different binding site from the substrate (tube model with C atoms in black).
  • FIG.2F shows interactions between compound 9 and DV2pro.
  • FIGS. 3A-E illustrate cellular and in vivo antiviral activities of compound 9.
  • FIGS. 3A-C show treatment of U87 cells with 9 caused dose-dependent reduction of RNA copies of ZIKV (FLR strain) (FIG. 3A), infectious ZIKV (FLR strain) (FIG. 3B), and infectious ZIKV (HN16 strain) (FIG. 3C).
  • FIG. 3D illustrates treatment with compound 9 significantly reduced ZIKV RNA in plasma (left) and brains (right) of ZIKV-infected mice.
  • FIG. 3E illustrates treatment with compound 9 significantly prolonged the survival of ZIKV-infected mice.
  • Dengue, West Nile, and Zika viruses belong to the genus Flavivirus in the Flaviviridae family of RNA viruses. These viruses are transmitted primarily by Aedes mosquitos. Four serotypes of dengue infect approximately 400 million people each year with 100 million developing dengue fever. Around 500,000 cases develop serious dengue hemorrhagic fever, causing about 22,000 deaths each year. Moreover, patients who recovered from one serotype are still susceptible to other serotypes with an increased likelihood of a more severe disease due to existing antibodies.
  • Zika has caused three major outbreaks in Pacific Ocean islands, Brazil, and other American countries, in which more than 1 million infections were reported and a large number of patients sought medical treatment. [0015] More seriously, Zika infection has been correlated with a 20-fold increased incidence of serious neurological disorders, including Guillain-Barré syndrome and more than 4,000 cases of microcephaly in newborns. Zika has quickly spread to 48 Pan-American countries, and has recently been found to be transmitted through sex or body fluids. The World Health Organization has announced that Zika is a public health emergency of international concern. However, despite these serious outcomes, as well as possible future outbreaks, there have been no antiviral drugs to prevent or treat Zika and dengue infections.
  • compositions that include various compounds.
  • the compositions of the present disclosure are in the form of compound 10, which can include various functional groups 12 (indicated as R1, R2, and R3).
  • compound 10 can include elements 14 (indicated as X, Y, and Z).
  • Additional embodiments of the present disclosure pertain to methods of treating a viral infection in a subject. In some embodiments illustrated in FIG.
  • the methods of the present disclosure include a step of administering a composition to a subject (step 20) to result in the inhibition of the virus in the subject (step 22).
  • the methods of the present disclosure are used to treat a viral infection caused by a flavivirus, such as, but not limited to, dengue virus, West Nile virus, Zika virus, tick-borne encephalitis virus, yellow fever virus, viruses causing encephalitis, insect-specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof.
  • a flavivirus such as, but not limited to, dengue virus, West Nile virus, Zika virus, tick-borne encephalitis virus, yellow fever virus, viruses causing encephalitis, insect-specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof.
  • compositions of the present disclosure can include various chemical configurations, functional groups, elements, and moieties. Furthermore, various methods may be utilized to treat various viral infections in various subjects.
  • compositions of the present disclosure can include various compounds.
  • the compositions of the present disclosure can include the following compound:
  • R1, R2, and R3 can each independently include, without limitation, hydrogen, aromatic groups, phenyl groups, benzyl, furan groups, phenyl furan groups, pyridine groups, phenyl pyridine groups, biphenyl groups, phenyl piperidine groups, pyrazole groups, amine groups, piperidine groups, amine groups, alkyl amine groups, aniline groups, methyl piperidine groups, benzene groups, cyclohexane groups, methyl benzoate groups, benzyl piperidine groups, imidazole groups, piperidine amine groups, -NHCH 3 groups, - CH(CH 3 )CH 2 CH 2 NH 2 groups, -NH 2 groups, furan, 3-phenylfuran, 2-phenylfuran, 3- phenyloxolane, phenylmethanamine, propan-2-ylbenzene, tert-butylbenzene, phenylpyrrolidine
  • Y can include, without limitation, N, CH, or combinations thereof.
  • Z can include, without limitation, N, CH, or combinations thereof.
  • m is an integer. In some embodiments, m is greater than or equal to 0.
  • the compounds in the compositions of the present disclosure can include, without limitation:
  • the compounds in the compositions of the present disclosure can include, without limitation:
  • the compounds in the compositions of the present disclosure can include, without limitation:
  • n is an integer. In some embodiments, n can include, without limitation, 0, 1, 2, 3, or 4. In some embodiments, the compounds in the compositions of the present disclosure can include, without limitation:
  • the compositions of the present disclosure are suitable for treating various viral infections in various subjects.
  • the viral infection is caused by a flavivirus, such as, but not limited to, dengue virus, West Nile virus, Zika virus, tick-borne encephalitis virus, yellow fever virus, viruses causing encephalitis, insect-specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof.
  • a flavivirus such as, but not limited to, dengue virus, West Nile virus, Zika virus, tick-borne encephalitis virus, yellow fever virus, viruses causing encephalitis, insect-specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof.
  • ZVpro linked or binary ZIKV protease
  • compositions of the present disclosure inhibit DENV serotype-2 protease (DV2pro), DENV serotype-3 protease (DV3pro), West Nile protease (WVpro), or combinations thereof.
  • the compositions of the present disclosure inhibit ZIKV replication.
  • the compositions of the present disclosure bind to an allosteric pocket of a flavivirus protease.
  • the compositions of the present disclosure are associated with a delivery agent.
  • the delivery agent is a nanoparticle.
  • the nanoparticles have diameters ranging from about 50 nm to about 500 nm.
  • the nanoparticles have diameters of about 100 nm to about 150 nm.
  • the nanoparticles can be, for example, polymeric nanoparticles, lipid-based nanoparticles, single wall or multiwall carbon nanotubes, fullerenes, and combinations thereof.
  • the compositions of the present disclosure include a solubilizing agent.
  • Solubilizing agents generally refer to one or more compounds that are capable of facilitating the solubilization of the compositions of the present disclosure in liquid formulations. Solubilizing agents may also be referred to as co-solvents or carriers.
  • the solubilizing agents include, but are not limited to, polyethylene glycol, glycerin, propylene glycol, ethanol, sorbitol, polyoxyethylated glycerides, polyoxyethylated oleic glycerides, polysorbates, sorbitan monooleate, hydroxypropyl-beta-cyclodextrin (HPCD), polyoxyl 40 hydrogenated castor oil, polyoxyl hydroxystearates, or combinations thereof.
  • the solubilizing agents of the present disclosure include water miscible organic solvents.
  • the solubilizing agents of the present disclosure include, without limitation, polyethylene glycol (e.g., PEG 400 and/or PEG 300), glycerin, propylene glycol, ethanol, sorbitol, polyoxyethylated glycerides (e.g., Labrafil M- 2125CS), polyoxyethylated oleic glycerides (e.g., Labrafil M-1944CS, Polyoxyl 35 castor oil, and/or Cremophor EL), polysorbates (e.g., polysorbate 20 and/or polysorbate 80), sorbitan monooleate, hydroxypropyl-beta-cyclodextrin (HPCD), polyoxyl 40 hydrogenated castor oil (i.e., Cremophor RH 40), polyoxyl hydroxystearates (e.g., Solutol HS 15), and combinations thereof.
  • polyethylene glycol e.g., PEG 400 and/or PEG 300
  • the compositions of the present disclosure can include at least one excipient agent.
  • the excipient agents can include, without limitation, anti- adherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, vehicles, or combinations thereof.
  • Treatment of Viral Infections in Subjects may be administered to various subjects in various manners to treat various viral infections in the subject. For instance, in some embodiments, the compositions of the present disclosure can be used to treat a viral infection caused by a flavivirus.
  • the flavivirus includes, but is not limited to, dengue virus, West Nile virus, Zika virus, tick-borne encephalitis virus, yellow fever virus, viruses causing encephalitis, insect-specific flaviviruses, cell fusing agent viruses, Palm Creek virus, Parramatta River virus, or combinations thereof.
  • the compositions of the present disclosure can treat a viral infection in a subject through various mechanisms. For instance, in some embodiments, the compositions of the present disclosure inhibit a viral protease. In some embodiments, the compositions of the present disclosure inhibit linked or binary ZIKV protease (ZVpro).
  • compositions of the present disclosure inhibit DENV serotype-2 protease (DV2pro), DENV serotype-3 protease (DV3pro), West Nile protease (WVpro), or combinations thereof.
  • the compositions of the present disclosure bind to an allosteric pocket of a flavivirus protease.
  • the compositions of the present disclosure inhibit viral replication.
  • Various methods may be utilized to administer the compositions of the present disclosure to a subject.
  • the administration occurs by a method that includes, without limitation, oral administration, inhalation, subcutaneous administration, intravenous administration, intra-nasal administration, intra-dermal administration, trans-dermal administration, intraperitoneal administration, intramuscular administration, intrathecal injection, topical administration, central administration, peripheral administration, transdermal administration, intraarterial administration, intracranial administration, intraspinal administration, intranasal administration, intraocular administration, intratumor administration, intramuscular administration, intranasal administration, subcutaneous administration, intra- or trans-dermal administration, intravenous administration, topical administration, or combinations thereof.
  • the compositions of the present disclosure can be administered to the subject via delivery agents.
  • the delivery agents can include various types of particles and/or targeting agents associated with the compositions of the present disclosure.
  • the delivery agents can be particles associated with the compositions of the present disclosure.
  • the delivery agent is a nanoparticle.
  • the compositions of the present disclosure can be administered to various subjects.
  • the subject is a human being suffering from a viral infection.
  • the viral infection is caused by a flavivirus.
  • the present disclosure can have various advantages. For instance, in some embodiments, the compositions of the present disclosure can exhibit significant anti-viral activities against various flaviviruses.
  • the compositions of the present disclosure can have IC50 values between 25 ⁇ M to 200 nM for various flavivirus proteases. In some embodiments, the compositions of the present disclosure can have IC50 values between 25 ⁇ M to 5 ⁇ M for various flavivirus proteases. In some embodiments, the compositions of the present disclosure can have IC 50 values between 5 ⁇ M to 200 nM for various flavivirus proteases. In some embodiments, the compositions of the present disclosure can have IC 50 values between 1 ⁇ M to 200 nM for various flavivirus proteases. In some embodiments, the compositions of the present disclosure can be broadly active inhibitors of flavivirus proteases with a high selectivity.
  • compositions of the present disclosure can be utilized in various manners and for various purposes.
  • the compositions of the present disclosure can be used for effectively treating various flavivirus infections in various subjects.
  • Additional Embodiments [0045] Reference will now be made to more specific embodiments of the present disclosure and experimental results that provide support for such embodiments. However, Applicants note that the disclosure below is for illustrative purposes only and is not intended to limit the scope of the claimed subject matter in any way. [0046] Example 1.1.
  • Flavivirus NS2B-NS3 Protease Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease [0047] This Example describes discovery, X-ray crystallography, and antiviral activity of allosteric inhibitors of flavivirus NS2B-NS3 protease.
  • Flaviviruses including dengue, West Nile and recently emerged Zika virus, are human pathogens, but there are no drugs to prevent or treat these viral infections.
  • the highly conserved flavivirus NS2B-NS3 protease is used for viral replication and therefore a drug target.
  • Dengue (DENV), West Nile and recently emerged Zika (ZIKV) viruses belong to the genus Flavivirus in the Flaviviridae family of RNA viruses. These viruses are transmitted primarily by Aedes mosquitos.
  • Four serotypes of DENV infect ⁇ 400 million people each year with 100 million developing dengue fever. ⁇ 500,000 cases develop serious dengue hemorrhagic fever, causing ⁇ 22,000 deaths each year.
  • patients recovered from one serotype are still susceptible to other serotypes with an increased likelihood of a more severe disease due to existing antibodies.
  • ZIKV has caused three major outbreaks in Pacific Ocean islands (2007 and 2013), Brazil and other American countries (2015-2016), in which >1 million infections were reported and a large number of patients sought medical treatment. More seriously, ZIKV infection has been correlated with a 20-fold increased incidence of serious neurological disorders, including Guillain-Barré syndrome and >4,000 cases of microcephaly in newborns. Since 2015, ZIKV has quickly spread to 48 pan-American countries. Recently, ZIKV was found to be transmitted through sex or body fluids. Despite these serious outcomes as well as possible future outbreaks, there have been no antiviral drugs to prevent or treat ZIKV and DENV infections.
  • ZIKV/DENV contain a single-stranded, positive-sense RNA with ⁇ 10,800 nucleotides, encoding a viral polyprotein.
  • the polyprotein is site-specifically cleaved by the viral NS2B-NS3 protease and several host proteases to produce functional proteins.
  • the NS2B-NS3 protease is used in viral replication and, therefore, a promising drug target.
  • flavivirus proteases A number of peptide-based covalent inhibitors of flavivirus proteases have been reported, but they did not demonstrate significant antiviral activities in cells or animal models due to low cell permeability and metabolic stability. Non-peptidic inhibitors have also been reported, but their inhibitory activities are relatively weak and how these compounds bind to the protease is unknown. [0051] Homology analysis showed flavivirus proteases are evolutionally conserved and highly stable. NS3 contains an N-terminal serine protease domain, but complexation with NS2B is required to become an active enzyme. Previous X-ray and NMR studies show the protease can adopt a“closed” or“open” conformation.
  • NS2B In the closed state that is catalytically active, NS2B is fully tied around NS3, and becomes part of the active site. In the open and inactive conformation, NS2B is partially bound to NS3 and far from the active site.
  • ZVpro Gly4-Ser-Gly4 linked and binary form of recombinant ZIKV protease
  • NS2B 47-95
  • NS3 (1-170)
  • ⁇ 1,200 compounds in Applicants' laboratory that were synthesized targeting histone modifying enzymes including lysine specific demethylase 1 (LSD1) were screened against the linked-ZVpro.
  • Compounds 1 and 2 were identified to be novel inhibitors with IC50 of 21.7 and 3.1 ⁇ M (Table 1). Table 1 shows structures and activity of compounds 1-9.
  • Table 1 shows structures and activity of compounds 1-9.
  • Scheme 1 shows the general synthesis for medicinal chemistry studies. 6-Chloro-2- aminopyrazine (10) was selectively iodized using N-iodosuccinimide, and the 2-amino group was converted to a hydroxyl, which was alkylated using a Mitsunobu reaction to give 12 with a protected piperidin-4-yl-methoxy group. Two selective Suzuki reactions were performed to introduce different aryl groups R 5 and R 6 to produce, after deprotection, compounds 3-5, 7 and 9. Mono-substitution of 1,6-dibromo-pyridine or -pyrazine (15) with (N-Boc-piperidin-4- yl)methylamine, followed by iodination produced the intermediate 16.
  • Compound 9 was found to be a potent inhibitor of the linked- and binary-ZVpro with IC 50 of 200 and 220 nM, respectively.
  • Table 1 and Table 2 summarize the inhibitory activities of selected analogs 3-8. Changing the -O- linkage at 2-position to an -NH- in 8 (IC 50 : 400 nM) resulted in a 2-fold activity reduction. Changing the central pyrazine ring in 8 to a pyridine in 6 (IC50: 790 nM) further reduced the potency. As compared with 7 (IC50: 530 nM) with a N-methyl secondary amine or 4 (IC50: 1.1 mM) with an amide at the 5-position, the primary amine in 9 is more favored.
  • Table 4 shows inhibitory activity of compound 9 against 5 human proteases, including serine proteases trypsin and dipeptidyl peptidase 4 (DPP4), aspartic protease pepsin, cysteine protease caspase-3, and metalloprotease matrix metalloprotease 8 (MMP-8).
  • DPP4 dipeptidyl peptidase 4
  • MMP-8 metalloprotease matrix metalloprotease 8
  • the U-shaped peptide segment is well organized in both the apo- and substrate-bound NS3.
  • residues 152-164 constitute part of the S1 and S2 pockets of the active site and have interactions with the substrate.
  • Inhibitor binding pushes the loops 71-75 and 117- 122 outwards by ⁇ 1.3 ⁇ and 3 ⁇ . All of these movements remodel the surface of NS3 and create a deep, L-shaped pocket (FIG. 2D) that accommodates the inhibitors.
  • the compounds are allosteric inhibitors, which do not occupy the substrate binding site (FIG. 2E). Mechanistically, these inhibitors bind to and stabilize DV2pro in the open conformation, which prevents NS2B from folding into the active site as well as the binding of the substrate.
  • Table 5 shows data collection and refinement statistics (molecular replacement). Table 5
  • FIGS.2D/F The inhibitor-protein interactions are illustrated in FIGS.2D/F.
  • the central pyrazine ring of 9 is located at the junction of the L-shaped pocket.
  • the furanylphenyl group is deeply inserted into the pocket with favorable hydrophobic interactions.
  • the 2- and 5-substituents occupy a deep surface groove, having mostly hydrophobic interactions.
  • the positively charged -NH 2 of 9 has hydrogen-bond and electrostatic interactions with Asp75, one of the protease catalytic triad.
  • TCID 50 tissue culture infective dose
  • compound 9 reduced infectious ZIKV viruses by 68% at 300 nM, 90% at 600 nM, 97% at 1.2 ⁇ M, 99% at 2.5 ⁇ M, and 99.7% at 5 ⁇ M.
  • Multiple experiments showed that EC68 of 9 was 300 or 600 nM.
  • Compound 9 exhibited similar antiviral activities against ZIKV HN16 strain (FIG. 3C). 9 also showed significant activity against DENV-2 (strain K0049), inhibiting viral replication in Vero cells by 97% at 5 ⁇ M.
  • DENV-2 strain K0049
  • results demonstrate compound 9 has potent cellular antiviral activity against Zika and dengue viruses.
  • cellular antiviral activities of compounds 1-9 are generally correlated with their biochemical activities against ZVpro (Table 1).
  • compound 9 is a broadly active inhibitor of flavivirus proteases and exhibits significant cellular and in vivo activities against Zika virus.
  • X-ray studies reveal that it binds to an allosteric pocket of NS3 and provide, for the first time, a druggable pocket of the flavivirus protease, as contrasted to the shallow active site recognizing polar and positively charged Arg or Lys of the substrate.
  • Example 1.2 Synthesis of Inhibitors
  • N-iodosuccinimide N-iodosuccinimide
  • Example 1.3 Constructs for Recombinant Proteins
  • Two expression plasmids for ZVpro were constructed according to reported methods. cDNA encoding NS2B (residues 47-95) and NS3 (residues 1-170) of Zika virus (GenBank: KU729217.2) connected with a Gly4-Ser-Gly4 linker was synthesized by GenScript. To avoid autoproteolytic cleavage, Arg95 of NS2B and Arg29 of NS3 were replaced by Ala and Gly, respectively. It was inserted into the NdeI/XhoI sites of pET-28a vector.
  • NS2B and NS3 were inserted into the NdeI/XhoI and NcoI/HindIII sites of pET-Duet-1 vector, respectively.
  • the pET-28a expression plasmids for DV2pro (GenBank: AY037116) including NS2B (residues 50-95) and NS3 (residues 1-182), DV3pro (GenBank: AAW66479) including NS2B (residues 50-95) and NS3 (residues 1-182), and WVpro (GenBank: AAV54504) including NS2B (residues 49-96) and NS3 (residues 2-184) were constructed similarly.
  • Example 1.4 Expression and Purification of Flavivirus Proteases
  • E. coli BL21 Rosetta strain, Agilent
  • protein expression was induced by adding 0.5 mM isopropylthiogalactoside at 18 °C for 20 hours. Cells were harvested, lysed, and centrifuged at 20,000 rpm for 20 min.
  • the supernatant was collected and applied to an affinity column chromatography using immobilized metal affinity chromatography (IMAC) beads (GE Healthcare).
  • IMAC immobilized metal affinity chromatography
  • the target protein was eluted with 300 mM imidazole buffer.
  • thrombin was added to the eluted fractions and the mixture was dialyzed against buffer containing 20 mM HEPES, 150 mM NaCl, 2 mM DTT, pH 7.5 for 20 hours. Subsequently, the protein was further purified to be >95% purity (SDS-PAGE) with a size-exclusion chromatography using a HiLoad 16/60 Superdex 75 column.
  • SDS-PAGE size-exclusion chromatography using a HiLoad 16/60 Superdex 75 column.
  • Activity and Inhibition Assays for Flavivirus Proteases Similar to a reported method, activity and inhibition assay for the linked- and binary- ZVpro was performed using the enzyme (1 nM) and benzoyl-norleucine-lysine-lysine-arginine 7- amino-4-methylcoumarine (Bz-Nle-Lys-Lys-Arg-AMC, 20 mM) as the substrate in a HEPES buffer (20mM, pH 7.3) containing 0.05% Triton X-100.
  • IC 50 triplicate samples of a compound with concentrations ranging from 1 nM to 10 mM were incubated with the enzyme for 10 min before adding the substrate to initiate the reaction in 96-well plate (100 ⁇ L final volume).
  • the initial velocity data were imported into Prism (version 5.0), and IC50 values from 3 independent experiments with standard deviation were obtained by using a standard dose-response curve fitting. Enzyme inhibition assays for DV2pro, DV3pro and WVpro were performed similarly.
  • the fluorescent assay kits for Dipeptidyl peptidase-4 (DPP4) and Caspase-3 were from BPS Bioscience. Inhibition of Matrix metalloproteinase 8 (MMP-8) was determined using SensoLyte 490 MMP-8 Assay Kit (AnaSpec). Pepsin and trypsin were purchased from Sigma. Their inhibition assay was performed using a FRET protease assay kit from Thermo Scientific. [00101] Example 1.7. Crystallization, X-Ray Data Collection and Structural Determination [00102] Recombinant DV2pro was expressed and purified as described above.
  • the protein was concentrated to 10 mg/mL in a buffer containing 20 mM Tris (pH 7.2) and 200 mM NaCl.
  • Co- crystallization with an inhibitor (5 mM) was set up by hanging drops with 1:1 ratio mixtures of 1 mL of protein solution and 1 mL of well solution containing 35% PEG 200, 100 mM MES, pH 8.5.
  • Crystals of the DV2pro-inhibitor complex were grown at 22 °C for 2 weeks, which were harvested in crystal freezing buffer containing 20% glycerol, 35% PEG 200, 100 mM MES, pH 8.5. The crystals were then flash-frozen in liquid N 2 for data collection.
  • X-ray diffraction data were collected at the Advanced Photon Source beamline 19-ID. Data were processed using HKL3000.
  • the initial molecular replacement structures were solved by program CCP4 PHASER using the coordinates of 2FOM as a template.
  • the program COOT was used for model building. Models of the inhibitors were built based on the difference maps.
  • the program CCP4 refmac was used for structure refinement.
  • the similes files of inhibitors were loaded onto CCP4 module sketcher to generate cif files.
  • the generated cif files were used in CCP4 refinement of the DV2pro-inhibitor structures.
  • the final refinement statistics were summarized in Table 4 and the coordinates were deposited into Protein Data Bank as entries 6MO0, 6MO1 and 6MO2.
  • Example 1.8. Cellular Antiviral Activity Testing [00104] Anti-ZIKV activity of compound 9 was evaluated in human U87 glioma cells, in which ZIKV replicates rapidly, but does not cause cytopathic effects (CPE. ZIKV also replicates rapidly in monkey Vero cells lacking interferon-mediated defense and causes significant CPE and cell lysis.
  • ZIKV FLR strain which was isolated from the serum of a patient infected in Colombia in 2015, was used for clinical relevance.
  • ZIKV HN16 strain Honduras, 2016
  • DENV K0049 strain Thailand, 1995
  • 2x10 4 U87 cells/well were seeded in 96-well plates and cultured in DMEM media with 2% FBS to form a monolayer of cells.0.01 MOI (multiplicity of infection) of ZIKV was added. After incubation for 1h, the supernatant was removed and cells were washed with PBS.
  • Viral RNA was extracted from the supernatant (50 ⁇ L) using TRIzol (ThermoFisher) according to the manufacturer’s instructions. qPCR is based on amplification of ZIKV envelope gene region 3, using ZIKV-specific primers and probes.
  • PCR was performed using a TaqMan Fast Virus 1-step Master Mix kit on a StepOnePlus RT-PCR system (Applied Biosystems). Concentrations of ZIKV RNA (copies/mL) were calculated by using a standard curve. Although this is a quick method to evaluate activity, only ⁇ 1/10 4 copies of RNA equals 1 TCID. Infectious ZIKV titer was determined with an end-point dilution assay. [00107] Example 1.10.
  • TCID50 tissue Culture Infectious Dose
  • Half-log serial dilution of the viral supernatant (50 ⁇ L) was added to a monolayer of Vero cells in quadruplicate in 96-well plates and cultured for 7 days. CPE/cell lysis was determined with microscope followed by MTT assay.
  • TCID 50 was calculated based on the highest dilution in which 350% (i.e., 32 out of the 4 quadruplicate wells) of Vero cells were infected with ZIKV. Compared to controls, the ability for a compound to reduce TCID50 can be determined. The results were from at least 2 independent experiments. [00109] Example 1.11.
  • Example 1.12. In Vivo Anti-ZIKV Activity Evaluation [00112] The animal studies were performed according to an approved animal protocol by IACUC of Applicants' institute. 100 TCID50 of ZIKV in 0.1 mL of medical grade saline was injected i.p.
  • Compound 9 in 0.1 mL of medical grade saline was injected i.p.1 h before virus inoculation. Medical grade saline was administered for the control group of mice. After treatment, mice were euthanized and their blood and brain samples were obtained and processed to determine copies of ZIKV RNA. The brain sample (90 mg) was homogenized in TRIzol (1 mL), centrifuged for 5 min, and the supernatant transferred to a fresh tube.
  • Example 1.13 Statistics
  • the significance of experimental differences in ZIKV RNA copies for in vivo studies was evaluated by use of the Student’s t test (Prism 5.0).
  • Example 1.14 Synthesis and Characterization of Compounds [00117] Scheme 4 illustrates a general method of synthesizing SYC-1110, 1598, 1622, 1617 and 1307.
  • N-iodosuccinimide N-iodosuccinimide
  • Reagents and conditions (i) tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, K 2 CO 3 , DMF, 100 °C, 12 h; (ii) N- Iodosuccinimide, CH 3 CN-DMSO, 24 h, 60% for 2 steps; (iii) 4-((N-Boc-amino)- methyl)phenylboronic acid, Pd(PPh3)4, Na2CO3, p-dioxane-H 2 O, 80 oC, 73%; (iv) 2-(4-(furan-3- yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, Pd(PPh 3 ) 4 , Na 2 CO 3 , p-dioxane-H 2 O, 100 oC, 78%; (v) HCl (4 N in p-dioxane), CH 2 Cl2, 0
  • Reagents and conditions (i) NaOH, MeOH, reflux; (ii) N-Boc-4-piperidinemethanol, PPh3, DIAD, THF; (iii) HCl (in p- dioxane), CH 2 Cl 2 , 0 oC, >90%.

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Abstract

Dans certains modes de réalisation, la présente invention se rapporte à des compositions qui inhibent des protéases de flavivirus. Dans d'autres modes de réalisation, la présente invention se rapporte à des méthodes de traitement d'une infection virale chez un sujet par l'administration des compositions de la présente invention au sujet. Dans certains modes de réalisation, l'infection virale est provoquée par un flavivirus tel que le virus de la dengue, le virus du Nil occidental, le virus Zika, le virus de la méningoencéphalite à tiques, le virus de la fièvre jaune, les virus provoquant une encéphalite, les flavivirus spécifiques des insectes, les virus d'agent de fusion cellulaire, le virus de Palm Creek, le virus de la rivière Parramatta, ou des combinaisons de ceux-ci.
PCT/US2020/027374 2019-04-09 2020-04-09 Nouveaux inhibiteurs de protéase de flavivirus pour la prévention et le traitement du zika, de la dengue et d'autres infections à flavivirus Ceased WO2020210428A1 (fr)

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WO2022246109A1 (fr) * 2021-05-21 2022-11-24 Gilead Sciences, Inc. Dérivés pentacycliques en tant qu'inhibiteurs du virus zika
WO2023177233A1 (fr) * 2022-03-16 2023-09-21 (주)아름테라퓨틱스 Nouveau composé et son utilisation pour inhiber la kinase de point de contrôle 2
EP4132508A4 (fr) * 2020-04-09 2024-06-26 Baylor College of Medicine Nouveaux inhibiteurs de l'histone acétyltransférase p300/cbp pour la thérapie du cancer
WO2024159284A1 (fr) * 2023-01-30 2024-08-08 Eurofarma Laboratórios S.A. Hydrazides inhibiteurs de nav 1.7 et/ou de nav 1.8, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses
WO2024159286A1 (fr) * 2023-01-30 2024-08-08 Eurofarma Laboratórios S.A. Composés phénoliques inhibiteurs de nav 1.7 et/ou de nav 1.8, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses
US12497408B2 (en) 2021-05-21 2025-12-16 Gilead Sciences, Inc. Tetracyclic compounds and methods for the treatment of Zika virus infection

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EP4132508A4 (fr) * 2020-04-09 2024-06-26 Baylor College of Medicine Nouveaux inhibiteurs de l'histone acétyltransférase p300/cbp pour la thérapie du cancer
WO2022246109A1 (fr) * 2021-05-21 2022-11-24 Gilead Sciences, Inc. Dérivés pentacycliques en tant qu'inhibiteurs du virus zika
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JP2024519910A (ja) * 2021-05-21 2024-05-21 ギリアード サイエンシーズ， インコーポレイテッド ジカウイルス阻害剤としての五環式誘導体
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JP7725617B2 (ja) 2021-05-21 2025-08-19 ギリアード サイエンシーズ， インコーポレイテッド ジカウイルス阻害剤としての五環式誘導体
US12497408B2 (en) 2021-05-21 2025-12-16 Gilead Sciences, Inc. Tetracyclic compounds and methods for the treatment of Zika virus infection
WO2023177233A1 (fr) * 2022-03-16 2023-09-21 (주)아름테라퓨틱스 Nouveau composé et son utilisation pour inhiber la kinase de point de contrôle 2
WO2024159284A1 (fr) * 2023-01-30 2024-08-08 Eurofarma Laboratórios S.A. Hydrazides inhibiteurs de nav 1.7 et/ou de nav 1.8, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses
WO2024159286A1 (fr) * 2023-01-30 2024-08-08 Eurofarma Laboratórios S.A. Composés phénoliques inhibiteurs de nav 1.7 et/ou de nav 1.8, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses

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